N-substituted imidazoles and their salts

ABSTRACT

CERTAIN IMIDAZOLES AND THEIR SALTS HAVING FUNGISTATIC PROPERTIES ARE PROVIDED WHICH HAVE THE FOLLOWING BASIC STRUCTURE:   IMIDAZOL-1-YL-C(-CH&lt;(-CH=CH-A=CH-CH=)&lt;(-1,2-PHENYLENE-   Y-1,2-PHENYLENE)   IN WHICH Y IS -(CH2)N-, -CH=CH-, O OR S; A IS N OR CH; AND N IS 0,1,2. TYPICAL FUNGI ARE TRICHOPYTON SPECIES, MICROSPORON SPECIES, CANDIDA SPECIES AND PENICILLIUM SPECIES. THESE COMPOUNDS ARE ALSO ACTIVE AGANIST PATHOGENIC PROTOZOA, VIRUSES AND BACTERIA.

United States Patent US. Cl. 260-309 21 Claims ABSTRACT OF THEDISCLOSURE Certain imidazoles and their salts having fungistaticproperties are provided which have the following basic structure:

in which Y is (CH --CH CH, O or S; A is N or CH; and n is 0, 1 or 2.Typical fungi are trichophyton species, Microsporon species, Candidaspecies and Penicillium species. These compounds are also active againstpathogenic protozoa, viruses and bacteria.

The present invention relates to certain new N-substituted imidazolesand salts thereof, to a process for their production and to theformulation and use thereof as pharmaceutical and fungistatic agents.

The present invention provides N-substituted imidazoles of the formula:

in which X is an alkyl or mercaptoalkyl radical or an electronegativesubstituent,

Y is -(CH -CH=CH, O or S,

A is N or CH,

m is 0, 1 or 2, and

n is 0, 1 or 2,

and pharmaceutically acceptable salts thereof.

When X is an alkyl or mercaptoalkyl radical it preferably has 1 to 4carbon atoms. When it is an electronegative substituent it may forexample be a halogen (fluorine, chlorine, bromine or iodine), or anitro, cyano or trifluoromethyl group.

3,647,816 Patented Mar. 7, 1972 "Ice When salts of the pharmaceuticalagents are to be used, they must be physiologically compatibleacceptable salts. Examples of inorganic acids yielding such saltsinclude the halogen hydracids, phosphoric acids, sulphonic acids,monoand dicarboxylic acids and hydroxy-carbonylic acids. Suitableexamples of organic acids are acetic acid, maleic acid, succinic acid,tartaric acid, lactic acid, citric acid, salicylic acid, sorbic acid andnaphthalene-di-sulphonic acid-1,5. The salts with halogen hydacids,particularly hydrochloric acid, lactic acid and salicylic acid are ofspecially important interest.

The invention also provides a process for the production of theN-substituted imidazoles of the invention which comprises reacting acompound of the formula:

in which X, Y, A and m have the above meanings, and Z is OH, chlorine orbromine, when Z is OH after reaction with a halogenating agent,optionally in the presence of an acid acceptor, with at least thetheoretically required amount of imidazole in a polar organic solvent ata temperature of 20 to 120 0., preferably at to C.

When the process is started from a compound in which Z is OH, then thehalogenation may be carried out in an inert organic solvent, such asether, petroleum ether, methylene chloride, benzene or toluene. Allreagents suitable for the halogenation of tertiary alcohols can be usedas halogenating agents, such as thionyl chloride, thionyl bromide,phosphoryl chloride, phosphoryl bromide, acetyl chloride and acetylbromide. The halogenation is normally effected with a temperature rangeof 0 to 100 C., preferably at 10 to 30 C., and after completion of thehalogenation the solvent is replaced by a polar solvent. In some casesit may be advantageous to carry out the halogenation itself in a polarsolvent directly followed, without intermediate isolation of the halideformed, by the reaction with the imidazole.

Suitable polar organic solvents include acetonitrile, nitromethane,acetone, diethyl ketone, dimethylformamide, dimethyl sulphoxide, etc.

In carrying out the reaction, the tri-substituted methyl halide may beslowly added to a solution of the imidazole which is either in solutionor in the solid form.

The reaction mixture may be worked up in conventional manner, forexample by concentrating or after diluting with water.

In a preferred method of carrying out the present proc- 27.6 -g. (0.1mol) of 9-(4-'fiuorophenyl)-fiuorenol-9 were dissolved in 250 ml. of drymethylene chloride and mixed at room temperature with 13.0 g. (0.11 mol)of thionyl chloride. The mixture was allowed to stand for 30 minutes,then boiled under reflux for minutes and concentrated. The solid residuewas washed with a little acetone and dried. Portions of the9-(4-fiuorophenyl)-9- chlorofluorene obtained in this way wereintroduced into a solution at 80 C. of 20 g. of imidazole in 150 ml. ofanhydrous acetonitrile. After 10 minues the hot solution was filtered,concentrated and the residue mixed with water. After suction-filtrationand trituraion of the residue with ether, 31 g. of a yellowish crudeproduct were obtained. Recrystallization from ethanol yielded 18.0 g.(55%) of colorless crystals of the formula:

5-pheny1-5-irnidazolyl- [a,d] dibenzocycloheptane 15.2 g. (0.05 mol) of5-phenyl-5-chloro-[a,dj-dibe11zocycloheptane were added in portions to aboiling solution of 6.8 g. (0.10 mol) of dry imidazole in acetonitrile.The mixture was boiled for 10 minutes and then cooled to 0 C. After theaddition of 100 ml. of ether, it was filtered 011 with suction. Theresidue was washed first with water and then with 100 ml. of ether. Thecombined ether filtrates were shaken out three times with portions of200 ml. of water, then dried and concentrated. The residue was mixedwith a little ethanol, cooled, filtered off with suction, washed with alittle cold ether, combined with 4 the filter residue first obtained,and dried. The total yield of the compound of the above formula: 13.1 g.(78%): white leaflets of M.P. 186187 C.

The starting compound was obtained as follows: 28.6 g. (0.10 mol) ofS-phenyl-S-hydroxy-[a,d]-dibenzocycloheptane were suspended in 100 m1.of dry methylene chloride and mixed with 13.8 g. (0.12 mol) ofthionylchloride. A vigorous S0 evolution started after a few minutes.The mixture was allowed to stand for 30 minutes, then boiled for 5minutes and concentrated. The residue was recrystallized from lightpetrol. There were obtained 24.4 g. of5-phenyl-5-chloro-[a,d]-dibenzocycloheptane of M.P. 115 C.(decomposition).

EXAMPLE 3 10-phenyl-10-imidazolyl-thioxanthene 29.0 g. (0.10 mol) of10-phenyl-lO-hydroxy-thioxanthene were boiled for one hour with 40 g. ofacetyl chloride in ml. of dry petroleum ether (40/60). The clearsolution was decanted from a small amount of an oily precipitate andconcentrated. The residue was taken up with 200 ml. of dry acetonitrileand the mixture boiled under reflux for 3 hours with 13.6 g. of dryimidazole. The mixture was subsequently concentrated, the residue mixedwith water, filtered off with suction and dried. The crude product wasrecrystallized from cyclohexane. Yield: 17.5 g. (57%) of10-phenyl-lfl-imidazolylthioxanthene of M.P. 179-181 C.

M.P. 197-199 C., which is compound (a) from Table 1, is produced in ananalogous manner to that described in the preceding examples.

EXAMPLE 5 The compound (VII) MP. 134-138 C., which is compound (f) fromTable 1, is produced in an analogous manner to that described in thepreceding examples.

EXAMPLE 6 The compound (VIII) M.P. 216-218 C., which is compound (k)from Table 1, is produced in an analogous manner to that described inthe preceding examples.

The same results were achieved when the chlorides were replaced bybromides as starting compounds.

The free N-substituted imidazoles were converted into their salts in theusual manner, for example by heating in acetonitrile with somewhat morethan the stoichiometrically required amount of the corresponding acidand subsequent isolation. The hydrochlorides are expediently obtained bypassing in hydrogen chloride into the solution of the imidazolederivative, for example in carbon tetrachloride.

The following salts of the compounds (c), (e), (k) and (l) have thestated melting points:

fumarate of (0): 182 C. (decomposition) hydrochloride of (e): startingat 90 C. (decomposition) tartrate of (k): 186 C. (decomposition)salicylate of (1): 137 C.138 C.

The new N-substituted imidazoles are valuable pharmaceutical agents.Their microbiological eifectiveness can be seen from the descriptionbelow.

In vitro on Sabourauds Milieu dEpreuve and in meat extract/ glucosebroth the new compounds exhibit a good fungistatic action against fungipathogenic to humans such as:

Trichophyton species, especially Trich. mem., Trick.

rubrum, Epidermophyton floccosum.

Microsporon species, especially M. canis, M. felineum and M. audouini.

Candida species, especially Candida albicans.

Further gemmiparous fungi, especially Cryptococci, Histoplasma andCoccidioides species.

Aspergilles, especially A. fumigatus, A. niger and A.

nidulans.

Penicillium species, especially Pen. commune.

Chromomycetes (Hormodendrum and Phialophora species).

The minimum inhibitory concentrations against some of the above fungiare given in Table 2 (in which the compounds are the indicated compoundsof Table 1).

TABLE 2 cam's Candida alb.

With Without With Without Asperg. Pam'- Compound serum serum serum serumniger cillin In vivo, the preparations were therapeutically applied asfollows:

(1) In an experiment carried out on white mice infected with Candida.When doses of 50-100 mg./kg. body weight were orally given onceor twicedaily, more than of the animals survived the infection, whereas -100% ofthe untreated infected control animals died due to the infection 6 daysp.i. The compounds (a), (d) and (f) of Table l were especially effectivein this experimental arrangement.

(2) In an experiment carried out on white mice infected withTrichophyton quinckeanum, the typical Quinckeanum dermatomycosis wastreated with the compounds (a), (d) and (f) with 2 mg./mouse orally perday mg./kg.). The course of the dermatomycosis was substantiallyshortened by this therapy; in a prophylactic experiment the developmentof the infection could be suppressed with the above-indicated dosage.

(3) When locally applied to guinea pigs infected with T rich. ment.particularly, for example, the compounds (a), (f), (g) and (k),dissolved 1% in dimethylsulphoxide/ glycerol, have a good therapeuticaction.

For humans the dosage amounts, on the average, to about 20 to about 60mg./kg. body weight, preferably 30 to about 50 mg./ kg. body weight,given at intervals of up to 12 hours for a period of about 12 to about20 days.

It may sometimes be necessary to deviate from the aforementionedquantities, depending for example on the method of application, theindividual reaction to the medicament, its formulation, and the momentof time or interval at which it is administered. It may thus besufficient in some cases to manage with less than the abovementionedminimum amount, whereas in other cases the indicated upper limit mayhave to be exceeded. If larger quantities are administered, it may beadvisable to distribute these in several individual doses over the day.

The chemotherapeutic agents can be used as such or in combination withpharmaceutically acceptable solid or liquid carriers. Suitable forms ofapplication, in combination with various inert carriers, are thefollowing: tablets, capsules, powders, sprays, aqueous suspensions,injectable solutions, elixirs, syrups and the like. Such carrierscomprise solid diluents (or fillers), a sterile aqueous medium,non-toxic organic solvents and the like. Tablets and the like intendedfor oral use may be provided with sweetening additives and similarsubstances. The therapeutically active compound should normally bepresent at a concentration of 0.5 to 90 percent by weight of the totalmixture, in quantities which are sufficient to achieve the range ofdosage mentioned above.

For oral application, the tablets can also contain additives, such assodium nitrate, calcium carbonate and dicalcium phosphate together withvarious other additives, such as starch (preferably potato stach) andthe like, and binding agents, such as polyvinylpyrrolidone, gelatin andthe like. Lubricants, such as magnesium stearate, sodium lauryl sulphateand talc may also be used concurrently for the production of thetablets. In the case of aqueous suspensions and/ or elixirs which areintended for oral use, the active substance may be provided with variousagents improving the flavor, coloring substances, emulsifiers and/ orother diluents, such as water, ethanol, propylene glycol, glycerol andsimilar compounds or combinations thereof.

In the case of parenteral application, solutions of the activesubstances in sesame or peanut oil, or in aqueous propylene glycol orN,N-dimethylformamide can be employed as well as sterile aqueoussolutions in the case of water-soluble compounds. Aqueous solutions ofthis kind should be buffered in the usual manner if necessary;furthermore, the liquid diluent should be rendered isotonic from thestart by the addition of the necessary amount of salt or glucose. Suchaqueous solutions are particularly suitable for intravenous,intramuscular and intraperitoneal injections. Sterile aqueous media ofthis kind may be prepared in known manner.

For topical application (e.g. solutions, creams, ointments) preferably aconcentration of about 0.5 to percent is used.

In the case of mice, rats, rabbits, dogs and cats the LD of the abovecompounds ranges from about 500 to 900 mg./kg. of body weight whenorally administered.

The invention therefore also provides a pharmaceutical compositioncomprising at least one of the new active compounds or salts inadmixture with a solid or liquid diluent or carrier.

The invention further provides a medicament in dosage unit formcomprising at least one of the new active compounds either alone or inadmixture with a solid or liquid diluent or carrier. The medicament mayinclude a protective envelope containing the active compound and, ifused, the diluent or carrier.

The term medicament in dosage unit form as used in the presentspecification means a medicament as defined above in the form ofdiscrete portions each containing a single or unit dose, or a multipleor sub-multiple of a unit dose of the active compound or compounds. Suchportions may, for example, be in monolithic coherent form, such astablets, suppositories, pills or dragees; in wrapped or concealed form,such as wrapped powders, cachets, sachets or capsules; in ampoules,either free or as a sterile solution suitable for parenteral injection;or in any other form known to the art.

In addition to their antimycotic activity, the compounds show goodactivity against pathogenic protoza, e.g. Trypanosoma, Trichomonas,Entamoeba Izz'stolytica, malaria parasites, Toxoplasma and againstviruses and bacteria, e.g. Staphylococci, streptococci, Klebsiella, E.coli. Further the compounds activate the granulation in wound heaing andshow a hypocholesterinaemic activity.

What is claimed is:

1. An N-substituted imidazole of the formula:

2. The compound of claim 1 which is 3. The compound of claim 1 which is4. The compound of claim 1 which is CH -CH il \/N (VIII) 5. The compoundaccording to claim 1, wherein X is 4-F, A is CH and m is l.

6. The compound according to claim 1, 4-Cl, A is CH and m is 1.

7. The compound according to claim 1, 4-Br, A is CH and m is 1.

8. The compound according to claim 1, 4-SCH A is CH and .m is 1.

9. The compound according to claim 1, 3-Cl, A is CH and m is 1.

10. The compound according to claim 1, 2-Cl, A is CH and m is 1.

11. The compound according to claim 1, wherein X is 4-F, Y is (CH A isCH and m is 1.

12. The compound according to claim 1, wherein X is 4-F, Y is -CH=CH-, Ais CH and m is 1.

13. The compound according to claim 1, wherein X is 4-Cl, Y is -CI-I=CH,A is CH and m is 1.

14. The compound according to claim 1, wherein X is 4-Br, Y is CH=CH, Ais CH and m is 1.

15. The compound according to claim 1, wherein X is 2-Cl, Y is CH=CH-, Ais CH and m is 1.

16. The compound according to claim 1, wherein X is 3-CF Y is CH=CH, Ais CH and m is 1.

17. The compound according to claim 1, wherein X is 3-Cl, Y is CH=CH--,A is CH and m is 1.

18. The compound according to claim 1, wherein X is 3-CF Y is CH CH A isCH and m is 1.

19. The compound according to claim 1, wherein X is 3-CF Y is -CH CH Ais CH and m is 1.

wherein X is wherein X is wherein X is wherein X is wherein X is 9 1020. The compound according to claim 1, wherein X is OTHER REFERENCES4-SCHs, Y 15 2- A 18 m 18 Blicke et al., J. Amer. Chem. Soc., vol. 58,pp. 559-62 21. The compound accordmg to claim 1, wherem X 1s (1936)QDLAS. a A is CH and m is Lester et al., J. Amer. Chem. Soc., vol. 68,pp. 375-80 5 (1946). QDLAS. References Cited Wittig et a1., Berichte,vol. 75, pp. 1491-1500 (1942). UNITED STATES PATENTS QDLD4- 3,530,1839/1970 K burz et a1 260309 NATALIE TROUSOF, P y E aminer 3,547,94212/1970 Godefroi et a1. 260-309 10 US. Cl. X.R. FOREIGN PATENTS 260-29OHL, 294.8 B, 296 T, 328, 335; 424263,

585,555 4/1960 Belgium 260-309 273

